U.S. patent number 5,438,043 [Application Number 08/081,334] was granted by the patent office on 1995-08-01 for beverage for preoperative intake.
This patent grant is currently assigned to Olle Ljungqvist Medical AB. Invention is credited to Olle Ljungqvist.
United States Patent |
5,438,043 |
Ljungqvist |
August 1, 1995 |
Beverage for preoperative intake
Abstract
A beverage for preoperative use is disclosed, which comprises
essentially of a hypotonic aqueous solution of a carbohydrate
mixture consisting of at least one member from each of the groups
mono-, di-, and polysaccharides in an amount of 8-20, preferably
9-15 g carbohydrates/100 ml solution. The invention also relates to
a hypotonic aqueous solution as defined above for the use as a
beverage for preoperative intake, to the use of mono-, di- and
polysaccarides for the preparation of such a hypotonic aqueous
solution and to the use of a dry substance comprising essentially
A) a carbohydrate mixture consisting of 10-30% by weight of at
least one monosaccharide, 10-30% by weight of at least one
disaccharide and at least one polysaccharide as the balance to 100%
by weight of said mixture and B) minor amounts of salts, flavoring
and preservatives for the preparation of a hypotonic beverage for
preoperative intake. Finally there is also disclosed a method for
suppressing the negative influence on patient carbohydrate
metabolism after surgery, and improving the defence capacity of the
patient upon bleeding in connection with or after the operation,
which method comprises preoperative oral administration to the
patient an effective amount of a hypotonic aqueous solution as
defined above.
Inventors: |
Ljungqvist; Olle (Stockholm,
SE) |
Assignee: |
Olle Ljungqvist Medical AB
(Bromma, SE)
|
Family
ID: |
20381301 |
Appl.
No.: |
08/081,334 |
Filed: |
June 21, 1993 |
PCT
Filed: |
December 20, 1991 |
PCT No.: |
PCT/SE91/00897 |
371
Date: |
June 21, 1993 |
102(e)
Date: |
June 21, 1993 |
PCT
Pub. No.: |
WO92/10947 |
PCT
Pub. Date: |
July 09, 1992 |
Foreign Application Priority Data
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|
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Dec 21, 1990 [SE] |
|
|
9004131 |
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Current U.S.
Class: |
514/23; 514/53;
514/54 |
Current CPC
Class: |
A23L
29/30 (20160801); A23L 2/38 (20130101) |
Current International
Class: |
A23L
1/09 (20060101); A61K 031/70 (); A61K
031/715 () |
Field of
Search: |
;514/23,53,54,58,60 |
References Cited
[Referenced By]
U.S. Patent Documents
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|
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4303684 |
December 1981 |
Pitchon et al. |
4734402 |
March 1988 |
Hashimoto et al. |
5032411 |
July 1991 |
Stray-Gundersen |
|
Foreign Patent Documents
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|
|
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0364053 |
|
Apr 1990 |
|
EP |
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WO-A1-9002494 |
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Mar 1990 |
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WO |
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WO-A1-9118610 |
|
Dec 1991 |
|
WO |
|
Primary Examiner: Henley, III; Raymond
Attorney, Agent or Firm: Darby & Darby
Claims
I claim:
1. A method for suppressing insulin resistance resulting from
surgical operation, and increasing available carbohydrate reserves
during or after surgery, which method comprises oral administration
within about four hours prior to surgical operation to a patient of
an effective amount of a hypotonic aqueous solution of between 8
and 20 grams of a carbohydrate mixture per 100 ml, said
carbohydrate mixture a monosaccharide, a disaccharide and a
polysaccharide.
2. The method of claim 1, wherein said mixture includes between 10
and 30 percent by weight monosaccharide; between 10 and 30 percent
by weight disaccharide; and balance polysaccharide.
3. The method of claim 1 further comprising an additive selected
from the group consisting of salts, flavorings, preservatives and
mixtures thereof.
4. The method of claim 1, wherein said solution includes from
between 9 and 15 grams of said mixture per 100 ml.
5. The method of claim 1, wherein said osmolality is between 250
and 295 mosm/kg.
6. The method of claim 1, wherein the pH is between 5.6 and
6.8.
7. The method of claim 5, wherein said osmolality is between 280
and 290 mosm/kg.
Description
This application is a 371 of PCT/SE91/00897, filed Dec. 20,
1991.
The present invention relates to a beverage intended for use before
elective surgery, and the use of a solution of carbohydrates as
such a beverage, and the use of carbohydrates or a carbohydrate
mixture for the preparation of such a beverage.
Approximately 2-300 000 elective (i.e. not emergency) surgical
operations under general anaesthesia are performed annually in
Sweden alone. A routine operation always brings about a relatively
long period (weeks) of convalescence for physical recovery.
Routinely, elective surgery is performed after a fasting period
beginning at midnight to the day of the operation. The effective
fasting period, however, lasts at least 16-18 hours, since the last
meal on the day before surgery is served around 16.00 h. The
obligatory fast before surgery has been introduced for reasons of
safety in connection with anaesthesia, primarily in order to
prevent the regurgitation of acid stomach content into the lungs,
and has not been considered to bring about any negative effects for
the patient.
However, a considerable change in the metabolism occurs already
during brief fasting, such as the pre-operative fasting period. The
most important alteration is the consumption of the carbohydrate
reserves of the body (primarily in form of glucose stored as
glycogen in the liver). The requirements of the brain for glucose,
however, remains unchanged during the first few days of fasting. In
order to satisfy this requirement during fasting, body metabolism
is changed so that new glucose can be produced. This is
accomplished by the degradation of carbohydrate reserves outside
the liver (mainly muscle), breakdown of proteins in muscle to amino
acids, mainly alanine and glutamine, as well as fat degradation.
The released substances are transported to the liver for new
glucose formation. In order to enable the degradation of energy
depots, the hormonal release is changed and thereby body metabolism
is changed from anabolism (augmenting energy loading and new tissue
building) into a state of catabolism (energy and tissue breakdown).
This shift in metabolism constitutes a normal part of body
metabolism, and is present after for example an over night sleep
with fasting. When the first meal is consumed in the morning, the
body responds with release of other hormones, primarily insulin,
which augments the storage of carbohydrates, proteins and fat.
Thus, even a brief fast, such as preoperative fasting, leads to two
essential changes in body metabolism. Both can be closely related
to the metabolism of carbohydrates:
1. Consumption of glucose reserves.
2. Change in body metabolism
These changes in metabolism has important consequences for the
responses to physical stress and trauma, as well as for the
recovery after stress and surgery.
It has been shown that exhaustion of the carbohydrate reserves
(glycogen) in the liver, which occurs already after brief fasting
(5-24 h in the rat and in man), has been shown to significantly
increase mortality after experimental hemorrhage and endotoxemia.
During hemorrhage, it has been proven that the glycogen reserve is
rapidly released as glucose to the circulation, where increased
glucose levels was registered. This increase in blood glucose
causes fluid mobilization from the greater reserves of fluid in the
body located inside the cells, into the circulation. The
development of increasing blood glucose levels thereby constitutes
an important part of the body's own defence during bleeding, and
this potential is markedly reduced after already a brief period of
fasting. This mechanism exists in the majority of mammals including
man. In accordance, the preoperative fasting period reduces the
availability of glucose in the body, and thus causes a considerable
reduction in this part of blood volume defence in case of
hemorrhage during of after surgery.
In all types of physical trauma (of which elective surgery is
perhaps the greatest in terms of volume) body metabolism is rapidly
changed. The normal balance between anabolism and catabolism is
markedly displaced towards catabolism. Of cardinal importance for
this change to develop, is the reduced effectiveness of the body's
major anabolic hormone insulin. The normal nutrient storing effects
of this hormone is markedly reduced, and a state of insulin
resistance is developed. It has been shown that the degree of
insulin resistance developing after surgery is related to the
magnitude of the operation performed (i.e. greater surgery leads to
greater insulin resistance). In addition, the normalization of
insulin action has been shown to take approximately three weeks
after routine abdominal surgery. As long as this resistance
remains, the body has difficulties in recovering. Therefore it is
desirable to reduce this development and to achieve a normal
balance in metabolism as quickly as possible after surgery.
The present invention is based on the finding that by preoperative
administration of a solution containing glucose, not only was the
defense in case of bleeding improved, but also was a significant
reduction (approximately 50%) in post operative development of
insulin resistance achieved. The present invention is thus based on
the fact that preoperative glucose administration improves post
operative metabolism.
To avoid fluid accumulation in the stomach upon drinking, the
beverage given must be specifically adjusted. Thus, hypo-osmolar
solutions have previously been shown to stimulate gastric emptying,
while hyperosmolar solutions have the reverse effect. Hence, any
fluid given shortly before surgery must be hypo-osmolar, preferably
below 295 mosm/kg. In addition, to reach maximum effect for fluid
defence in case of hemorrhage as well as reaching maximum metabolic
effect, a maximum of carbohydrates should be administrated. To
accomplish this, the carbohydrates should be adjusted accordingly
by appropriate mixture of mono-, di- and poly- saccharides. In
addition, by adjusting the pH of the beverage above that of stomach
fluids, the pH of the stomach content can be elevated. This is also
of importance in case of regurgitation of stomach content during
anaesthesia.
More particularly, the present invention is based on the following
findings:
A. Animal experiments
Survival after a 42% blood loss was studied in twenty rats fasted
for 24 h. As fasting started, all animals were allowed free access
to water until 17.00 h the day before hemorrhage. From this time
until 8.00 h on the day of experiment water was withheld. The rats
were randomly divided into two groups drinking either 7-11 ml of
tap water or approximately the same volume of hypo-osmolar fluid,
rich in carbohydrates (for details see Example 1 below). After
drinking this fluid volume, the animals were subjected to 42% blood
loss in a standardized manner. All but one animal (n=5) receiving
water died within 3 h of completion of hemorrhage, while 8/9 rats
given carbohydrates recovered completely during the seven day
observation period, difference between groups, p<0.05, Fisher's
exact test.
These experiments are in agreement with other experiments were
approximately the same amount of carbohydrates were infused
intravenously prior to hemorrhage. Infusion of saline resulted in
100% mortality in ten rats, while another ten given glucose all
survived. In parallel experiments six rats in each group were
sacrificed immediately prior to hemorrhage for analysis. Liver
glycogen content in glucose infused rats was 578.+-.72 .mu.mol/g
dry liver wt compared to 104 .mu.mol/g dry liver wt in the other
group, difference significant, p<0.01 (Mann Whitney U-test).
During hemorrhage, glucose treated rats developed blood glucose
levels of 16.1.+-.0.9 mmol/l compared to saline treated 5.2.+-.0.1
mmol/l, p<0.01. This increase in blood glucose resulted in
improved fluid movement into the circulation, as indicated by the
lower hematocrits in glucose treated rats 35.+-.1% vs 40.+-.1% in
saline treated, p<0.01.
The hormone response to hemorrhage was investigated in two groups
of rats fasted for 24 h before hemorrhage. The groups were
pretreated according to the above protocol. Pretreatment with
glucose resulted in a hormone pattern with increased insulin levels
in a way which has previously been described only in rats subjected
to hemorrhage in the fed state. This insulin response was not
present in saline treated rats, and has previously been shown not
to develop if glucose treatment is commenced once the bleeding has
started. This finding indicates that important parts of the effects
of glucose administration can only be achieved if treatment is
given prior to the onset of stress.
With greater glucose release and higher blood glucose levels during
hemorrhage, fluid movement is improved during blood loss. This in
turn has direct effects on survival after hemorrhage. In a series
of experiments in 24 h fasted rats (8-10 in each group), this
finding was confirmed by infusions of glucose solutions of various
concentrations during the course of hemorrhage. The concentrations
were 0%, 5%, 10%, 20% and 30%. With increasing glucose
concentration given, blood glucose developments increased. This in
turn resulted in a stepwise improvement of fluid movement into the
circulation, and ultimately recovery after hemorrhage. Thus,
survival with a 0% solution was 12.5%, 5% was 33.3%, 10% was 58.3%,
20% was 66.7% and 30% was 75%. This finding illustrates that the
possibility to develop increasing glucose levels in blood during
hemorrhage is an important determinant for survival after
hemorrhage.
B Clinical experiments
In 12 patients, healthy apart from gallstone and operated for
cholecystectomy, were randomly allocated into receiving either
glucose 5 mg/kg/min intravenously from 18.00 h the day before
surgery, until start of the operation, or no infusion during this
period (e.g. routine per-operative fasting period). Insulin
sensitivity (m-value) was determined using the euglycemic
hyperinsulinemic clamp technique within 3 days prior to surgery,
and on the first post-operative day. The pre-operative M-values
were similar in both groups (n=6); 4.64.+-.1.36 mg glucose/kg/min
in glucose treated patients and 4.31.+-.0-35 mg/kg/min in fasted
patients, difference not significant. Post-operative M-value was
significantly lower (p<0.02) in fasted patients (2.00.+-.0.21
mg/kg/min) compared to patients pre-treated with glucose
(3.14.+-.0.88 mg/kg/min). This finding shows that pre-treatment
with glucose during pre-operative fasting significantly reduces the
post operative disturbance in body metabolism by reducing the
development of post-operative insulin resistance.
In another study, patients operated for gallstone disease were
pre-treated with either glucose infusion (5 mg/kg/min) or
traditional fasting before the same operation. During the
operation, small pieces of tissue were sampled from the liver for
the analysis of the content of glycogen (e.g. glucose polymers) as
well as the activity of enzymes involved in the control of the
hepatic metabolism of carbohydrates. Patients treated with glucose
had higher content of glycogen, and the enzymatic setting was
adjusted in a way which is more associated with that seen after
meal intake (than that seen after fasting), compared to the
patients fasted before surgery. This difference in hepatic
enzymatic adjustment has experimentally been shown to be associated
with marked differences in post-stress metabolism. Enzymatic
adjustment, such as that found after food intake was associated
with improved post-stress metabolism.
In accordance with the above, the present invention involves a
beverage specifically designed for pre-operative use. The beverage
contains a mixture of mono-, di-, and polysaccharides. The purpose
of pre-operative carbohydrate supplementation is, such has been
described above, to increase the carbohydrate reserves in the body
and simultaneously adjust body metabolism towards a more anabolic
setting by the time of surgery. Treatment accomplishing these
effects have been shown to markedly reduce the level of disturbance
in body metabolism caused by surgical operations and improve organ
function after surgery. By the intake of carbohydrates in larger
amounts, a shift in body metabolism is accomplished, whereby the
metabolism of the body is shifted towards anabolism and substrate
loading, which in turn, has been shown to be closely associated
with improved responses to physical stress and surgery. By oral
intake of carbohydrates, the storage of carbohydrates into the
liver is improved compared to intravenous supplementation. The
amount of glycogen in the liver has been shown to be one important
determinant of the capability for defence during stress. By careful
adjustment of the different carbohydrate components used in the
beverage, the beverage may be given orally without increased risk
during anaesthesia and surgery. The beverage is to be consumed
during the evening before surgery and/or 30 min-4 h, preferably 1-3
h before start of the operation.
The beverage according to the present invention is characterized in
that it comprises essentially a hypotonic aqueous solution of a
carbohydrate mixture consisting of at least one member from each of
the groups mono-, di-, and polysaccharides in an amount of 8-20,
preferably 9-15 g carbohydrates/100 ml solution.
According to a preferred embodiment of the beverage according to
the invention, the composition of the carbohydrates is 10-30,
preferably 12-21 per cent of at least one monosaccharide, 10-30,
preferably 20-25 per cent by weight of at least one disaccharide
and at least one polysaccharide as the balance to 100 per cent by
weight calculated on the weight of the mixture. The mutual weight
ratios between mono-, di-, and poly-saccharides are adjusted to
render the aqueous solution hypotonic.
Examples of monosaccharides to be contained in the mixture of
carbohydrates are glucose and/or fructose.
Saccharose and/or maltose is/are used preferably used as the
disaccharide(s). Examples of polysaccharides to be contained in the
carbohydrate mixture are starch, maltodextrins and/or dextrins. The
polysaccharide or polysaccharides should, of course, be soluble in
water and be physiologically innocuous.
The beverage according to the invention should suitably have an
osmolality of 250-295 mosm/kg, preferably 280-290 mosm/kg.
In addition to the carbohydrate mixture, the beverage can,
according to the invention, contain salts, flavoring, and
preservatives. As salts in this connection, sodium chloride and/or
potassium chloride may be mentioned. The amount of salt is usually
below 200 mg/100 ml solution, preferably 80 mg/100 ml solution.
The beverage is produced and packed in volumes of 100 ml-500 ml.
Different pack sizes of the beverage is produced to adjust the
fluid intake for patients of varying weights. In addition, a larger
volume should be given during the evening before the operation, and
a smaller volume 30 min-4 h, preferably 1-3 h prior to start of
surgery. The former is given to increase the supply of
carbohydrates, while the latter, apart from this, also will trigger
a hormonal response in the body, thereby adjusting the patients
metabolism into a more anabolic setting. The mixture of
carbohydrates may also be produced as a dry substance, and packed
in suitable sterile bags to be solved in water immediately before
use.
The invention also relates to a hypotonic aqueous solution of a
carbohydrate mixture consisting of at least one member from each of
the groups mono-, di- and poly-saccharides in an amount of 8-20,
preferably 9-15 g carbohydrates/100 ml solution for use as a
beverage for preoperative intake. Said hypotonic aqueous solution,
in addition to the carbohydrate mixture, preferably contains minor
amounts of salts, flavoring and preservatives.
The invention further relates to the use of a dry substance
comprising essentially A) a carbohydrate mixture consisting of
10-30, preferably 12-21 per cent by weight of at least one
monosaccharide, 10-30, preferably 20-25 per cent by weight of at
least one disaccharide, and at least one polysaccharide as the
balance to 100 per cent by weight calculated on the weight of the
carbohydrate mixture and B) minor amounts of salts, flavoring and
preservatives for the preparation of a hypotonic beverage for
preoperative intake.
The invention also relates to the use of carbohydrates selected
from the groups mono-, di- and poly-saccharides for the preparation
of a hypotonic aqueous solution of at least one member of each of
said groups for preoperative intake, which solution comprises 8-20,
preferably 9-15 g carbohydrates/100 ml solution.
The invention also relates to a method for suppressing the negative
influence of an operation on carbohydrate metabolism of the patient
after surgery and improving the defense capacity of the patient
upon bleeding in connection with or after the operation, which
method comprises preoperative oral administration to the patient of
an effective amount of a hypotonic aqueous solution of a
carbohydrate mixture consisting of at least one member from each of
groups mono-, di- and poly-saccharides in an amount of 8-20,
preferably 9-15 g carbohydrates/100 ml solution.
The invention is further illustrated by the following examples, to
which however, the invention should not be limited. These examples
represent the best mode contemplated at present for carrying out
the invention.
EXAMPLE 1
A beverage is produced using conventional methods, containing a
total of 10 g carbohydrates, of which 5.5 g are dextrin
(polysaccharide, Dextrin type 1: from corn (9004-53-9), Sigma
Chemicals, St Louis, USA), 2.5 g maltose (disaccharide) and 2.0 g
glucose (monosaccharide), with 0.075 g NaCl per 100 ml solution
with an osmolality of approximately 280 mosm/kg and the pH is 6.2,
with the addition of NaOH 1M 0.02 ml per 100 ml solution. The
beverage is packed to a volume of 400 ml. The beverage is intended
to be consumed by a person weighing 70 kg, approximately 3-4 h
prior to start of surgery.
EXAMPLE 2
A beverage is produced by conventional methods to contain 14.7 g
carbohydrates/100 ml solution. The mixture of carbohydrates
contains 11.7 g dextrin (polysaccharide, Dextrin type 1: from corn
(9004-53-9), Sigma Chemicals, St Louis, USA.), 1.5 g maltose
(disaccharide) and 1.5 g glucose (monosaccharide), and 0.075 g NaCl
is added. The osmolality of the beverage is approximately 255
mosm/kg, and the pH 6.0, adjusted with the addition of 1M NaOH
0.026 ml/100 ml solution. The beverage is packed into two volume
sizes, 500 ml and 100 ml. The larger volume is intended for a
patient weighing 75 kg, to be consumed during the evening prior to
operation, and the smaller volume approximately 2-3 h prior to the
operation.
EXAMPLE 3
A dry substance of carbohydrates is produced by conventional mixing
means, containing 14.7 g carbohydrates. The mixture of
carbohydrates contains 11.7 g dextrin (polysaccharide, Dextrin type
1: from corn (9004-53-9), Sigma Chemicals. St Louis, USA), 1.5 g
maltose (disaccharide) and 1.5 g glucose (monosaccharide), and
0.075 g NaCl is added. To adjust the pH of the final solution NaOH
1M 0.04 ml is added to the dry substance, which is then dried. The
dry substance is intended to be dissolved to yield 100 ml solution
with an osmolality of 285 mosm/g and pH 6.0. The beverage is
intended to be consumed approximately 3 h prior to the operation,
by a person weighing 70-75 kg.
* * * * *